Attenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts

Abstract

Lymphoid T-zone fibroblastic reticular cells (FRCs) actively promote T-cell trafficking, homeostasis, and expansion but can also attenuate excessive T-cell responses via inducible nitric oxide (NO) and constitutive prostanoid release. It remains unclear how these FRC-derived mediators dampen T-cell responses and whether this occurs in vivo. Here, we confirm that murine lymph node (LN) FRCs produce prostaglandin E 2 (PGE 2 ) in a cyclooxygenase-2 (COX2)-dependent and inflammation-independent fashion. We show that this COX2/PGE 2 pathway is active during both strong and weak T-cell responses, in contrast to NO, which only comes into play during strong T-cell responses. During chronic infections in vivo, PGE 2 -receptor signaling in virus-specific cluster of differentiation (CD)8 cytotoxic T cells was shown by others to suppress T-cell survival and function. Using COX2 flox/flox mice crossed to mice expressing Cre recombinase expression under control of the CC chemokine ligand (CCL19) promoter (CCL19cre), we now identify CCL19 + FRC as the critical source of this COX2-dependent suppressive factor, suggesting PGE 2 -expressing FRCs within lymphoid tissues are an interesting therapeutic target to improve T-cell–mediated pathogen control during chronic infection.

LN-Derived Fibroblastic Reticular Cells and Their Impact on T Cell Response—A Systematic Review

“…The host characteristics in the articles included in this review, such as source, genotype, age, and gender, are described in Table 1 , along with the types and times of interventions used to analyze fibroblastic reticular cell functions. The hosts used in the majority of the studies reviewed here were C57BL/6 mice (79%) [ 18 , 19 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 32 , 33 , 34 , 37 , 38 , 39 , 40 , 41 ]. There were 10 studies (53%) that used some type of genetically modified mice [ 21 , 22 , 25 , 28 , 30 , 32 , 33 , 35 , 38 , 40 ], of which 40% were NOD scid gamma (NSG) mice [ 21 , 25 , 33 , 35 ] and 60% were RAG deficient mice [ 22 , 28 , 30 , 32 , 33 , 35 ].…”

“…The articles reviewed here report on using several animal models of disease and/or genetically modified mice as tools to investigate FRCs’ effect on T cells. These articles also approach and clarify the mechanisms involved in T cell proliferation or differentiation in subsets with regulatory, effector, or memory profiles [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. In addition, these articles reported the markers used to identify and isolate FRCs, as well as the methods used for these cells’ cultivation.…”

In Vitro Suppression of T Cell Proliferation Is a Conserved Function of Primary and Immortalized Human Cancer-Associated Fibroblasts

“…Our results show that both Im-CAFs and their parental CAFs are capable of inhibiting T cell proliferation, and for the first time that CAFs exerted a conserved T cell suppressive effect across various solid tumor types, at least in vitro. However, T cell suppression is not unique to CAFs; rather, it appears to be a conserved property of activated fibroblasts [ 60 , 61 , 62 , 63 , 64 ], supporting the possibility that this observation is likely to be relevant to human biology and the development of new therapeutics. These early proof-of-concept findings indicate that the Im-CAFs are a key tool that can provide further insights into the underlying mechanisms of CAF-mediated T cell suppression, and to explore further effects on T cell function, including changes to methylation state, differentiation, cytokine production, and tumor cell killing.…”

Lymph Node Stromal Cells: Mapmakers of T Cell Immunity

“…In agreement, the genetic deletion of IL-33 in FRCs results in impaired LCMV-specific CD8 + T cell responses both in terms of frequencies and IFNγ and TNFα production [ 95 ]. On the other hand, expression of the cyclooxygenase-2 (COX2) and its product prostaglandin E 2 (PGE 2 ) by FRCs upon viral infection result in an inhibition of the T cell response ( Figure 2 B) [ 96 ]. As the modulation of CD28 or IL-2 signaling does not overcome the attenuation of virus-specific T cell responses by FRC-derived COX2 and PGE2, it has been proposed that the pathway directly affects TCR signaling, leading to T cell exhaustion and increasing viral load [ 96 ].…”